The present invention relates to arylsulfonanilide derivatives and their use as pharmacologically active agents capable of lowering plasma cholesterol levels and inhibiting abnormal cell proliferation.
A number of arylsulfonamides have recently been described for the treatment of disorders and conditions arising from abnormal cell proliferation and from elevated plasma cholesterol levels. See, for example, PCT publications WO 97/30677 and WO 98/05315.
Most prevalent among diseases stemming from abnormal cell proliferation is cancer, a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer. The most commonly used types of anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, flutamide). The ideal antineoplastic drug would kill cancer cells selectively, with a wide therapeutic index relative to its toxicity towards non-malignant cells. It would also retain its efficacy against malignant cells, even after prolonged exposure to the drug. Unfortunately, none of the current chemotherapies possess an ideal profile. Most possess very narrow therapeutic indexes and, in practically every instance, cancerous cells exposed to slightly sublethal concentrations of a chemotherapeutic agent will develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents.
Psoriasis, a common chronic skin disease characterized by the presence of dry scales and plaques, is generally thought to be the result of abnormal cell proliferation. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes. Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeutic cure exists for psoriasis. Milder cases are often treated with topical corticosteroids, but more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. bacteria, trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds.
Accordingly, it is one object of the present invention to provide compounds which directly or indirectly are toxic to actively dividing cells and are useful in the treatment of cancer, viral and bacterial infections, vascular restenosis, inflammatory diseases, autoimmune diseases, and psoriasis.
A further object of the present invention is to provide therapeutic compositions for treating said conditions.
Still further objects are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions. A further object is to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders.
Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.
The invention provides novel arylsulfonanilide compounds, as well as methods and compositions relating to novel arylsulfonanilides and their use as pharmacologically active agents. The compounds and compositions find use as pharmacological agents in the treatment of disease states, particularly hypercholesterolemia, atherosclerosis, cancer, bacterial infections, and psoriasis, or as lead compounds for the development of such agents. The compounds of the invention have the formula: 
or a pharmaceutically acceptable salt thereof.
In one group of embodiments the letter Y in the above formula represents a linear or cyclic peptide having from four to fourteen amino acid residues or a radical of formula xe2x80x94Aaxe2x80x94Z, wherein Aa is an amino acid or dipeptide residue and Z is selected from hydrogen, xe2x80x94CHO, 
For the radicals above, the symbols R5, R6 and R7 are each independently hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, heteroaryl(C1-C4)alkyl and heteroaryl(C1-C4)heteroalkyl. Optionally, R5 and R6 are linked together to form a 5- or 6-membered ring. The symbol R8 represents (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl or aryl (C1-C4)heteroalkyl. The symbols R9 and R10 are independently hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl and aryl(C1-C4)heteroalkyl, and are optionally linked together to form a 5- or 6-membered ring.
Returning to the general formula above, the symbols R1 and R4 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)heteroalkyl. The symbols R2 and R3 are each independently hydrogen, halogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, xe2x80x94OR11, xe2x80x94SR11 and xe2x80x94NR11R12, wherein R11 and R12 are each independently hydrogen, (C1-C8)alkyl and (C1-C8)heteroalkyl. When R2 and R3 are attached to adjacent carbon atoms, they are optionally linked together to form a fused 5-, 6- or 7-membered ring.
The symbol Ar represents a substituted aryl group selected from 
in which X1 and X2 are each independently F, Cl or Br.
The methods of the present invention use pharmaceutical compositions containing compounds of the foregoing description of the general Formula I for the treatment of pathology such as cancer, bacterial infections, psoriasis, hypercholesterolemia, atherosclerosis, pancreatitis, and hyperlipoproteinemia. Briefly, the inventions involve administering to a patient an effective formulation of one or more of the subject compositions.
Definitions
The term xe2x80x9calkyl,xe2x80x9d by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multi-radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term xe2x80x9calkyl,xe2x80x9d unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9calkylene.xe2x80x9d The term xe2x80x9calkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by xe2x80x94CH2CH2CH2CH2xe2x80x94. Typically, an alkyl group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A xe2x80x9clower alkylxe2x80x9d or xe2x80x9clower alkylenexe2x80x9d is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
The term xe2x80x9calkoxy,xe2x80x9d employed alone or in combination with other terms means, unless otherwise stated, an alkyl group, as defined above, connected to the remainder of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers.
The term xe2x80x9cthioalkoxy,xe2x80x9d employed alone or in combination with other terms means, unless otherwise stated, an alkyl group, as defined above, connected to the remainder of the molecule via a sulfur atom, such as, for example, thiomethoxy (methylthio), thioethoxy (ethylthio), 1-thiopropoxy, 2-thiopropoxy and the higher homologs and isomers.
The term xe2x80x9cheteroalkyl,xe2x80x9d by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multi-radicals, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)2xe2x80x94CH3xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94CH3, xe2x80x94Si(CH3)3, xe2x80x94CH2xe2x80x94CHxe2x95x90Nxe2x80x94OCH3, and xe2x80x94CHxe2x95x90CHxe2x80x94N(CH3)xe2x80x94CH3. Up to two heteroatoms may be consecutive, such as, for example, xe2x80x94CH2xe2x80x94NHxe2x80x94OCH3 and xe2x80x94CH2xe2x80x94Oxe2x80x94Si(CH3)3. Also included in the term xe2x80x9cheteroalkylxe2x80x9d are those radicals described in more detail below as xe2x80x9cheteroalkylenexe2x80x9d and xe2x80x9cheterocycloalkyl.xe2x80x9d The term xe2x80x9cheteroalkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, as well as all other linking groups described herein, no specific orientation of the linking group is implied.
The terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9cheterocycloalkylxe2x80x9d, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of xe2x80x9calkylxe2x80x9d and xe2x80x9cheteroalkylxe2x80x9d, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
The term xe2x80x9caryl,xe2x80x9d employed alone or in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The rings may each contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The aryl groups that contain heteroatoms may be referred to as xe2x80x9cheteroarylxe2x80x9d and can be attached to the remainder of the molecule through a carbon atom or a heteroatom. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl ring systems are selected from the group of acceptable substituents described below.
The terms xe2x80x9carylalkylxe2x80x9d and xe2x80x9carylheteroalkylxe2x80x9d are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, 1-naphthyloxy-3-propyl, and the like). The arylalkyl and arylheteroalkyl groups will typically contain from 1 to 3 aryl moieties attached to the alkyl or heteroalkyl portion by a covalent bond or by fusing the ring to, for example, a cycloalkyl or heterocycloalkyl group. For arylheteroalkyl groups, a heteroatom can occupy the position at which the group is attached to the remainder of the molecule. For example, the term xe2x80x9carylheteroalkylxe2x80x9d is meant to include benzyloxy, 2-phenylethoxy, phenethylamine, and the like.
Each of the above terms (e.g., xe2x80x9calkyl,xe2x80x9d xe2x80x9cheteroalkylxe2x80x9d and xe2x80x9carylxe2x80x9d) are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: xe2x80x94ORxe2x80x2, xe2x95x90O, xe2x95x90NRxe2x80x2, xe2x95x90Nxe2x80x94ORxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, -halogen, xe2x80x94SiRxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94OC(O)NRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94NRxe2x80x3C(O)2Rxe2x80x2, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NH, xe2x80x94NRxe2x80x2C(NH2)xe2x95x90NH, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, xe2x80x94CN and xe2x80x94NO2 in a number ranging from zero to (2N+1), where N is the total number of carbon atoms in such radical. Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 each independently refer to hydrogen, unsubstituted(C1-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When Rxe2x80x2 and Rxe2x80x3 are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, xe2x80x94NRxe2x80x2Rxe2x80x3 is meant to include 1-pyrrolidinyl and 4morpholinyl.
Similarly, substituents for the aryl groups are varied and are selected from: -halogen, xe2x80x94ORxe2x80x2, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94Rxe2x80x2, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94OC(O)NRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94NRxe2x80x3C(O)2Rxe2x80x2, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NH, xe2x80x94NRxe2x80x2C(NH2)xe2x95x90NH, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, xe2x80x94N3, xe2x80x94CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C1-C4)alkyl.
Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94Txe2x80x94C(O)xe2x80x94(CH2)qxe2x80x94Uxe2x80x94, wherein T and U are independently xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94 or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94Axe2x80x94(CH2)rxe2x80x94Bxe2x80x94, wherein A and B are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2NRxe2x80x2xe2x80x94 or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94(CH2)sxe2x80x94Xxe2x80x94(CH2)txe2x80x94, where s and t are independently integers of from 0 to 3, and X is xe2x80x94Oxe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94S(O)2NRxe2x80x2xe2x80x94. The substituent Rxe2x80x2 in xe2x80x94NRxe2x80x2xe2x80x94 and xe2x80x94S(O)2NRxe2x80x2xe2x80x94 is selected from hydrogen or unsubstituted (C1-C6)alkyl.
As used herein, the term xe2x80x9cheteroatomxe2x80x9d is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
For the compounds of the invention which contain amino acid or peptide fragments, the amino acid residues are denoted by three letter designations following conventional practices. The designations for gene-encoded amino acids are as follows: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val). Commonly encountered amino acids which are not gene-encoded may also be used in the present invention. These amino acids include omithine (Orn), t-butylglycine (t-BuG), phenylglycine (PhG), cyclohexylalanine (Cha), norleucine (Nle), N-methylisoleucine (N-MeIle), homoarginine (Har), sarcosine (Sar), and xcex2-alanine (xcex2-Ala). All of the amino acids used in the present invention may be either the D- or L-isomer. The term xe2x80x9camino acid residuexe2x80x9d is meant to include that portion of an amino acid that remains upon incorporation into a peptide or compound via convention amide links. For example, a glycine residue can be represented as xe2x80x94COxe2x80x94CH2xe2x80x94NHxe2x80x94. Similarly, a xcex2-alanine residue can be represented as xe2x80x94COxe2x80x94CH2CH2xe2x80x94NHxe2x80x94.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al, xe2x80x9cPharmaceutical Saltsxe2x80x9d, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula I. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
General
The compounds described herein are related to compounds provided in PCT publications WO 97/30677 and WO 98/05315, and to compounds provided in co-pending application Ser. No. 08/917,025 (filed Aug. 22, 1997) to application Ser. No. 60/090,681 filed Jun. 25, 1998. More particularly, compounds are now described having an attached amino acid/peptide group.
Embodiments of the Invention
The present invention provides novel arylsulfonanilide derivatives having the formula: 
or a pharmaceutically acceptable salt thereof.
In the above formula, the letter Y represents either a linear or cyclic peptide having from four to fourteen amino acid residues or a radical of formula -Aa-Z, wherein Aa is an amino acid or dipeptide residue and Z is selected from hydrogen, xe2x80x94CHO, 
Turning first to those embodiments in which Y is a linear or cyclic peptide, preferred peptides will have from five to nine amino acid residues. A variety of amino acids are useful in the present invention, including the gene-encoded, naturally-occurring L-amino acids and their D-isomers, and non-gene encoded amino acids such as, for example, ornithine, t-butylglycine, phenylglycine, cyclohexylalanine, norleucine, 2-thienylalanine, N-methylisoleucine, homoarginine, Nxcex1-methylarginine, sarcosine, and xcex2-alanine. Further preferred are those embodiments in which Y represents a cyclic peptide having from five to nine amino acid residues. As used herein, the term xe2x80x9ccyclic peptidexe2x80x9d is meant to include those in which all of the amino acids are present in the cyclic portion, and those in which only a portion of the amino acids form a ring. Additionally, the ring or cyclic portion can be formed via disulfide linkages between cysteine residues in the peptide, or by more amide bond formation. In the latter group of embodiments, the cyclic peptide can be joined to the remainder of the molecule via a carboxylic acid group which is either present in the non-cyclized portion of the peptide, or via a carboxylic acid residue which is part of an amino acid side chain (e.g., aspartic acid or glutamic acid). The term xe2x80x9clinear or cyclic peptidexe2x80x9d is also meant to include those peptides in which the N-terminus is capped with an acyl group such as, for example, acetyl, pivaloyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Particularly preferred cyclic peptides are the pentapeptides -Cys-Arg-Gly-Asn-Cys-NHAc (SEQ ID NO:1) and -Cys-Arg-Gly-Asp-Cys-NHAc (SEQ ID NO:2) in which a disulfide link joins the two cysteine residues. Another particularly preferred cyclic peptide is the nonapeptide -Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys-NHAc (SEQ ID NO:3) in which a dissulfide link joins Cys1 to Cys7 or Cys9, or Cys3 to Cys7 or Cys9.
For those embodiments in which Y represents -Aa-Z and Z is one of the radicals above, the symbols R5, R6 and R7 are each independently hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, heteroaryl(C1-C4)alkyl and heteroaryl(C1-C4)heteroalkyl. Optionally, R5 and R6 are linked together to form a 5- or 6-membered ring. The symbol R8 represents (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl or aryl(C1-C4)heteroalkyl. The symbols R9and R10 are independently hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl and aryl(C1-C4)heteroalkyl, and are optionally linked together to form a 5- or 6-membered ring.
In one group of embodiments, Y represents 
Preferred amino acid and residues (Aa) are those derived from glycine, serine, threonine, aspartic acid, xcex2-alanine, alanine, histidine and arginine, with amino acid residues from glycine, serine and threonine being the most preferred. Also preferred are those embodiments in which Aa is a dipeptide residue derived from Ser-Gly, Thr-Gly, Gly-Ser, and Gly-Thr. Still further preferred are those embodiments in which R5, R6 and R7 are each independently hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl, aryl(C1-C4)alkyl, or aryl(C1-C4)heteroalkyl. Most preferred are those embodients in which R5 and R6 are hydrogen and R7 is selected from hydrogen, (C1-C8)alkyl, aryl, or aryl(C1-C4)alkyl.
In another group of embodiments, Y represents -Aa-CO2R8. In this group of embodiments, preferred amino acid and dipeptide residues are derived from glycine, serine, threonine, aspartic acid, xcex2-alanine, alanine, histidine, arginine, Ser-Gly, Thr-Gly, Gly-Ser and Gly-Thr. Capping the N-terminus of the amino acid and dipeptide residues is xe2x80x94CO2R8. Preferably, R8 is (C1-C8)alkyl or aryl(C1-C4)alkyl. More preferably, R8 is methyl, ethyl, isopropyl, propyl, t-butyl, isobutyl, benzyl or 2-phenylethyl.
In still another group of embodiments, Y is 
Preferred amino acid and dipeptide residues are those that have been described above. R9 and R10 are selected to provide a stable urea with the N-terminal amino group of Aa. Accordingly, R9 and R10 are independently selected from hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl and aryl(C1-C4)heteroalkyl, and are optionally linked together to form a 5- or 6-membered ring. Preferably, R9 and R10 are hydrogen, (C1-C8)alkyl, or aryl(C1-C4)alkyl, more preferably, hydrogen, methyl, ethyl, or benzyl. Optionally, R9 and R10 are combined, with the nitrogen atom to which each is attached, to form a 5- or 6-membered ring such as, for example, a pyrrolidine, piperidine, pyridazine or morpholine ring.
In yet another group of embodiments, Y is 
Preferred amino acid and dipeptide residues have been described above. Preferred groups for R5 and R6 include hydrogen, (C1-C8)alkyl, (C1--C8)heteroalkyl, aryl, aryl(C1-C4)alkyl, or aryl(C1-C4)heteroalkyl. Still further preferred are those embodiments in which R5 is hydrogen and R6 is hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, or aryl(C1-C4)alkyl. In further preferred embodiments, the alkyl groups are optionally substituted with, for example, xe2x80x94OH, xe2x80x94SH, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94NH2, xe2x80x94OCH3, xe2x95x90O, or xe2x80x94NHC(xe2x95x90NH)xe2x80x94NH2. Preferred groups for R9 and R10 are hydrogen, (C1-C8)alkyl, or aryl(C1-C4)alkyl, more preferably, hydrogen, methyl, ethyl, acetyl, propionyl, benzoyl or benzyl. As above, in certain embodiments, R9 and R10 are combined, with the nitrogen atom to which each is attached, to form a 5- or 6-membered ring.
Returning to the general formula I, above, the symbols R1 and R4 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)heteroalkyl. Preferably, R1 and R4 are each independently hydrogen or (C1-C4)alkyl. More preferably, R1 and R4 are both hydrogen.
The symbols R2 and R3 independently represent hydrogen, halogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, xe2x80x94OR11, xe2x80x94SR11 or xe2x80x94NR11R12, wherein R11 and R12 are each independently hydrogen, (C1-C8)alkyl and (C1-C8)heteroalkyl. When R2 and R3 are attached to adjacent carbon atoms, they are optionally linked together to form a fused 5-, 6- or 7-membered ring. In one group of preferred embodiments, R2 and R3 are attached to adjacent carbon atoms C3 and C4 (relative to C1 which bears the sulfonamido group, and C5 which bears xe2x80x94N(R4)Y). In other preferred embodiments, R2 is selected from hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy and (C1-C3)thioalkoxy. In still other preferred embodiments, R3 is selected from hydrogen, (C1-C3)alkyl, xe2x80x94OR11, xe2x80x94SR11 and xe2x80x94NR11R12 wherein R11 and R12 are each independently hydrogen, (C1-C3)alkyl and (C1-C3)heteroalkyl.
The symbol Ar represents a substituted aryl group selected from 
in which X1 and X2 are each independently F, Cl or Br. In one group of preferred embodiments, Ar is pentafluorophenyl. In another group of preferred embodiments, Ar is 2,3,4,5-tetrafluorophenyl. In yet another group of preferred embodiments, Ar is 3,4,5-trimethoxyphenyl. In still another group of preferred embodiments, Ar is 3-methoxy-4,5-methylenedioxyphenyl.
Certain combinations of the above preferred embodiments are particularly preferred. In a first group of preferred embodiments, the compounds have the formula: 
In this group of embodiments, R2 is preferably hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy or (C1-C3)thioalkoxy, more preferably, methyl, methoxy, ethoxy or thiomethoxy. R4 is preferably hydrogen or (C1-C4)alkyl, more preferably hydrogen or methyl. Aa is preferably Gly, Ser, Thr, Asp, Ala, xcex2-Ala, His, Arg, Ser-Gly, Gly-Ser, Thr-Gly, or Gly-Thr, most preferably Gly, L-Ser, D-Ser, L-Thr or D-Thr. Z is preferably hydrogen, acetyl, benzyloxycarbonyl, t-butyloxycarbonyl, trifluoroacetyl, N,N-dimethylcarbamoyl, N-methylcarbamoyl or carbamoyl.
In another preferred combination, the compounds have the formula: 
In this group of embodiments, preferred groups for R2, R4, Aa and Z are those that have been described for formula Ia.
Yet another group of particularly preferred embodiments is represented by formula Ic: 
Preferred groups for R2, R4, Aa and Z are those that have been described for formula Ia.
Still another group of preferred embodiments are represented by formula Id. 
Preferred groups for R2, R4, Aa and Z are again those that have been described for formula Ia.
Synthesis
Compounds of the present invention can be prepared using certain intermediates and methods described in WO 97/30677 and WO 98/05315. In one group of embodiments, arylsulfonamidoanilines can be prepared as described, and the anilino amino group can then be acylated with an appropriate amino acid or peptide derivative using traditional amide bond formation reactions. For example, 2-methoxy-5-pentafluorophenylsulfonamidoaniline can be treated with a suitably protected amino acid (e.g., N-xcex1-BOC-O-benzyl-L-serine, N-BOC-glycine, N-acetyl-glycine, N-BOC-L-aspartic acid xcex1-tbutyl ester, N-BOC-xcex2-alanine, N-BOC-D-alanine, N-acetyl-L-histidine, and the like) in the presence of such coupling agents as HOBT and HBTU to form compounds of the present invention. In a similar manner, additional compounds can be formed beginning with the appropriate aniline derivative.
Following coupling of the amino acid or peptide to the sulfonamidoaniline fragment, the amino group of the amino acid or peptide portion can be further derivatized to provide, for example, a carbamate, amide or urea terminus. Procedures useful to conduct these transformations are well known in the synthesis literature for peptide derivatization. For example, treatment of the amino group with an appropriate isocyanate produces urea terminus. Similarly, treatment of the amino group with a carboxylic acid (acetic acid, propionic acid, benzoic acid, and the like) under standard acylation conditions provides an amide terminus. Alternatively, the amino acid or peptide used in preparing the compounds of the present invention can be suitably derivatized prior to coupling to the sulfonamidoaniline.
The compounds used as initial starting materials in this invention may be purchased from commercial sources or alternatively are readily synthesized by standard procedures which are well know to those of ordinary skill in the art.
Some of the compounds of Formula I may exist as stereoisomers, and the invention includes all active stereoisomeric forms of these compounds. In the case of optically active isomers, such compounds may be obtained from corresponding optically active precursors using the procedures described above or by resolving racemic mixtures. The resolution may be carried out using various techniques such as chromatography, repeated recrystallization of derived asymmetric salts, or derivatization, which techniques are well known to those of ordinary skill in the art.
The compounds of the invention may be labeled in a variety of ways. For example, the compounds may contain radioactive isotopes such as, for example, 3H (tritium) and 14C (carbon-14). Similarly, the compounds may be advantageously joined, covalently or noncovalently, directly or through a linker molecule, to a wide variety of other compounds, which may provide pro-drugs or function as carriers, labels, adjuvents, coactivators, stabilizers, etc. Such labeled and joined compounds are contemplated within the present invention.
Analysis of Compounds
Representative compounds and compositions were demonstrated to have pharmacological activity in in vitro assays, e.g., they are capable of specifically modulating a cellular physiology to reduce an associated pathology or provide or enhance a prophylaxis.
Certain preferred compounds and compositions are capable of specifically regulating LDL receptor gene expression. Compounds may be evaluated in vitro for their ability to increase LDL receptor expression using western-blot analysis, for example, as described in Tam et al. (J. Biol. Chem. 1991, 266, 16764). Established animal models to evaluate hypocholesterolemic effects of compounds are known in the art. See, for example, Spady et al., J. Clin. Invest. 1988, 81, 300, Evans et al., J. Lipid Res. 1994, 35, 1634 and Lin et al., J. Med. Chem. 1995, 38, 277.
Certain preferred compounds and compositions display specific toxicity to various types of cells. Certain compounds and compositions of the present invention exert their cytotoxic effects by interacting with cellular tubulin. For certain preferred compounds and compositions of the present invention, that interaction is covalent and irreversible. Other compounds bind in a non-covalent manner. Compounds and compositions may be evaluated in vitro for their ability to inhibit cell growth, for example, as described in Ahmed et al., J. Immunol. Methods 1994, 170, 211. Established animal models to evaluate antiproliferative effects of compounds are also known in the art. For example, compounds can be evaluated for their ability to inhibit the growth of human tumors grafted into immunodeficient mice using methodology similar to that described by Rygaard and Povlsen, Acta Pathol. Microbiol. Scand. 1969, 77, 758, and Giovanella and Fogh, Adv. Cancer Res. 1985, 44, 69.
Formulation and Administration of Compounds and Pharmaceutical Compositions
The present invention provides methods of using the subject compounds and compositions to treat disease or provide medicinal prophylaxis, to slow down and/or reduce the growth of tumors, to upregulate LDL receptor gene expression in a cell, or to reduce blood cholesterol concentration in a host, etc. These methods generally involve contacting the cell with or administering to the host an effective amount of the subject compounds or pharmaceutically acceptable compositions.
The compositions and compounds of the invention and the pharmaceutically acceptable salts thereof can be administered in any effective way such as via oral, parenteral or topical routes. Generally, the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending on the disease target, the patient, and the route of administration. Preferred dosages are administered orally or intravenously in the range of about 0.05 mg/kg to about 20 mg/kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day.
In one embodiment, the invention provides the subject compounds combined with a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc. to form pharmaceutically acceptable compositions. The compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages. Useful carriers include solid, semi-solid or liquid media including water and non-toxic organic solvents.
In another embodiment, the invention provides the subject compounds in the form of a pro-drug, which can be metabolically converted to the subject compound by the recipient host. A wide variety of pro-drug formulations are known in the art.
The compositions may be provided in any convenient form including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, etc. As such the compositions, in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers. For example, dosage units may be included in a variety of containers including capsules, pills, etc.
The compositions may be advantageously combined and/or used in combination with other hypocholesterolemic or antiproliferative therapeutic or prophylactic agents, different from the subject compounds. In many instances, administration in conjunction with the subject compositions enhances the efficacy of such agents. Examplary antiproliferative agents include cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine, vinblastine, vinarelbine, paclitaxel, docetaxel, tamoxifen, flutamide, hydroxyurea, and mixtures thereof. Exemplary hypocholesterolemic and/or hypolipemic agents include: bile acid sequestrants such as quaternary amines (e.g. cholestyramine and colestipol); nicotinic acid and its derivatives; HMG-CoA reductase inhibitors such as mevastatin, pravastatin, and simvastatin; gemfibrozil and other fibric acids, such as gemfibrozil, clofibrate, fenofibrate, benzafibrate and cipofibrate; probucol; raloxifene and its derivatives; and mixtures thereof.
The compounds and compositions also find use in a variety of in vitro and in vivo assays, including diagnostic assays. For example, various allotypic LDL receptor gene expression processes may be distinguished in sensitivity assays with the subject compounds and compositions, or panels thereof. In certain assays and in in vivo distribution studies, it is desirable to used labeled versions of the subject compounds and compositions, e.g. radioligand displacement assays. Accordingly, the invention provides the subject compounds and compositions comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.